Adopting the Rumsfeld approach to understanding the action of levodopa and apomorphine in Parkinson's disease.

Dopaminergic therapies dominate the treatment of the motor and non-motor symptoms of Parkinson's disease (PD) but there have been no major advances in therapy in many decades. Two of the oldest drugs used appear more effective than others-levodopa and apomorphine-but the reasons for this are seldom discussed and this may be one cause for a lack of progress. This short review questions current thinking on drug action and looks at whether adopting the philosophy of ex-US Secretary of State Donald Rumsfeld reveals 'unknown' aspects of the actions of levodopa and apomorphine that provide clues for a way forward. It appears that both levodopa and apomorphine have a more complex pharmacology than classical views would suggest. In addition, there are unexpected facets to the mechanisms through which levodopa acts that are either forgotten as 'known unknowns' or ignored as 'unknown unknowns'. The conclusion reached is that we may not know as much as we think about drug action in PD and there is a case for looking beyond the obvious.

Optimised endoscopic access for intrajejunal levodopa application in idiopathic Parkinson's syndrome.

Pump-guided intrajejunal levodopa administration is one of the indispensable forms of therapy in advanced Parkinson's syndrome, along with deep brain stimulation and subcutaneous apomorphine injection. The standard application of levodopa gel via a JET-PEG, i.e. a percutaneous endoscopic gastrostomy (PEG) with an inserted internal catheter into the jejunum, has not been unproblematic due to the restricted absorption area of the drug in the region of the flexura duodenojejunalis and especially due to the sometimes considerable accumulated complication rates of a JET-PEG. Causes of complications are mainly a non-optimal application technique of PEG and internal catheter as well as the often missing adequate follow-up care. This article presents the details of a-compared to the conventional technique-modified and optimised application technique, which has been clinically proven successfully for years. However, many details derived from anatomical, physiological, surgical and endoscopic aspects must be strictly observed during the application to reduce or avoid minor and major complications. Local infections and buried bumper syndrome cause particular problems. The relatively frequent dislocations of the internal catheter (which can ultimately be avoided by clip-fixing the catheter tip) also prove to be particularly troublesome. Finally, using the Hybrid technique, a new combination of an endoscopically controlled gastropexy with 3 sutures and subsequent central thread pull-through (TPT) of the PEG tube, the complication rate can be dramatically reduced and thus a decisive improvement achieved for patients. The aspects discussed here are highly relevant for all those involved in the therapy of advanced Parkinson's syndrome.

Randomized controlled trials on the use of cannabis-based medicines in movement disorders: a systematic review.

Anecdotal references, preclinical, and non-randomized studies support the therapeutic potential of cannabinoids for movement disorders (MD). To create an evidenced-based point of view for patients and physicians, we performed a systematic review of randomized controlled trials (RCT) on the use of cannabinoids in MD. The seven RCTs found on PD used different cannabis formulations. No improvement of motor symptoms was shown in any of the two RCTs with this as primary outcome (PO), but in the nabilone group, an improvement in quality of life was documented. Of the three RCTs having levodopa-induced dyskinesia as PO, only one using nabilone showed a reduction. Anxiety and anxiety-induced tremor could be reduced in the cannabidiol group as well as anxiety and sleeping problems in the nabilone group in another RCT. In two RCTs with Tourette syndrome, an improvement in tics was revealed. From three RCTs on Huntington's disease only one found symptoms relief using nabilone. No reduction of dystonia could be shown in the two included RCTs. The limited number of available but small and inhomogeneous RCTs precludes reliable conclusions. Therefore, more and smartly designed RCTs are urgently needed.

Gastrointestinal involvement in Parkinson's disease: pathophysiology, diagnosis, and management.

Growing evidence suggests an increasing significance for the extent of gastrointestinal tract (GIT) dysfunction in Parkinson's disease (PD). Most patients suffer from GIT symptoms, including dysphagia, sialorrhea, bloating, nausea, vomiting, gastroparesis, and constipation during the disease course. The underlying pathomechanisms of this α-synucleinopathy play an important role in disease development and progression, i.e., early accumulation of Lewy pathology in the enteric and central nervous systems is implicated in pharyngeal discoordination, esophageal and gastric motility/peristalsis impairment, chronic pain, altered intestinal permeability and autonomic dysfunction of the colon, with subsequent constipation. Severe complications, including malnutrition, dehydration, insufficient drug effects, aspiration pneumonia, intestinal obstruction, and megacolon, frequently result in hospitalization. Sophisticated diagnostic tools are now available that permit more detailed examination of specific GIT impairment patterns. Furthermore, novel treatment approaches have been evaluated, although high-level evidence trials are often missing. Finally, the burgeoning literature devoted to the GIT microbiome reveals its importance for neurologists. We review current knowledge about GIT pathoanatomy, pathophysiology, diagnosis, and treatment in PD and provide recommendations for management in daily practice.

Implications of dopaminergic medication withdrawal in Parkinson's disease.

The trajectory of the use of dopamine replacement therapy (DRT) in Parkinson's disease (PD) is variable and doses may need to be increased, but also tapered. The plan for dose adjustment is usually done as per drug information recommendations from the licensing bodies, but there are no clear guidelines with regards to the best practice regarding the tapering off schedule given sudden dose reductions of drugs such as dopamine agonists may have serious adverse consequences. A systematic literature search was, therefore, performed to derive recommendations and the data show that there are no controlled studies or evidence-based recommendations how to taper or discontinue PD medication in a systematic manner. Most of the data were available on the dopamine agonist withdrawal syndrome (DAWS) and we found only two instructions on how to reduce pramipexole and rotigotine published by the EMA. We suggest that based on the available data, levodopa, dopamine agonists (DA), and amantadine should not be discontinued abruptly. Abrupt or sudden reduction of DA or amantadine in particular can lead to severe life-threatening withdrawal symptoms. Tapering off levodopa, COMT inhibitors, and MAO-B inhibitors may worsen motor and non-motor symptoms. Based on our clinical experience, we have proposed how to reduce PD medication and this work will form the basis of a future Delphi panel to define the recommendations in a consensus.

An updated calculator for determining levodopa-equivalent dose.

Calculation of levodopa-equivalent dose in Parkinson's disease has become common in research, but is also a useful tool in clinical practice, especially when initiating device-aided treatments (deep brain stimulation, apomorphine and levodopa infusions). The aim with the present calculator is to provide an updated conversion table, including dose calculation of the recently developed levodopa/entacapone/carbidopa intestinal gel infusion. Future versions of the calculator should be made conducive to learning by means of artificial intelligence.

Effectiveness of botulinum neurotoxin type A injections in naïve and previously-treated patients suffering from Torti- or Laterocollis or -caput: Results from a German-Austrian open-label prospective post-marketing surveillance study.

AbobotulinumtoxinA (aboBoNT-A; Dysport®) is an effective treatment for cervical dystonia (CD) with a well-established safety profile. In this prospective, multicentre, non-interventional study (NCT01840462) the primary objective was effectiveness (Tsui score) of aboBoNT-A in botulinum neurotoxin type A (BoNT-A) treatment-naïve and previously-treated (>2 yrs) patients after two injection cycles (at visit 3). Secondary objectives included the effectiveness of aboBoNT-A overall visits and quality of life (CDQ-24) in different CD subtypes. Observation time was 12-16 months, including 5 visits and 4 injection cycles (each 3-4 months). In the analysis population 273 patients from 41 centres across Germany and Austria were included. At baseline, 62.6% were previously-treated with BoNT-A. The major primary components of CD were torticollis (64.5%) and torticaput (17.6%). Previously-treated patients showed a slight reduction of the Tsui scores, whereas BoNT-A-naïve patients had a more severe baseline Tsui score and improved much more over all cycles. Results were similar for CDQ-24. Interestingly, improvements mainly occurred in the Tsui subscore A (amplitude of sustained posture). Marked differences between CD subtypes regarding effectiveness could not be determined. To our knowledge this is the first large multi-centre study investigating the effectiveness of BoNT-A in different primary subtypes of CD over several injection cycles.

[King's Parkinson's disease pain scale : Intercultural adaptation in the German language]. / King's Parkinson's Disease Pain Scale : Interkulturelle Adaption in deutscher Sprache.

BACKGROUND: Pain is a frequent symptom of idiopathic Parkinson's disease and has a substantial impact on quality of life. The King's Parkinson's disease pain scale (KPPS) has become internationally established and is an English-language, standardized, reliable and valid scale for evaluation of pain in idiopathic Parkinson's disease. This article presents a validated version in German. METHOD: The German translation was adapted interculturally and developed using an internationally recognized procedure in consultation with the authors of the original publication. The primary text was first translated by two bilingual neuroscientists independently of one another. Thereafter, the two versions were collated to generate a consensus version, which was accepted by the translators and preliminarily trialled with 10 patients. Hereafter, the German version was re-translated back into English by two other neurologists, again independently of one another, and a final consensus was agreed on using these versions. This English version was then compared with the original text by all of the translators, a process which entailed as many linguistic modifications to the German version as the translators considered necessary to generate a linguistically acceptable German version that was as similar as possible to the original English version. After this test text had been subsequently approved by the authors, the German text was applied to 50 patients in two hospitals, and reviewed as to its practicability and comprehensibility. RESULTS: This work led to the successful creation of an inter-culturally adapted and linguistically validated German version of the KPPS. DISCUSSION: The German version presented here is a useful scare for recording and quantifying pain in empirical studies, as well as in clinical practice.

[Nonmotor symptoms in Parkinson's disease]. / Nichtmotorische Symptome beim Morbus Parkinson.

Parkinson's disease is a neurodegenerative disease that affects the peripheral and central nervous system. In addition to the motor symptoms, a large number of nonmotor symptoms, which are of high clinical relevance, occur in all disease stages. Particular attention has been paid to neuropsychiatric and autonomic disorders in recent years. Among the neuropsychiatric disorders are depression, cognitive loss as well as psychoses and impulsive control disorders. Regarding autonomic function, all areas can be affected, with cardiovascular, gastrointestinal and urogenital disorders and symptoms being the most common. Therapy is difficult and requires an interdisciplinary approach. There is a considerable diagnostic and therapeutic need in the field of nonmotor disorders.

[Pharmacological treatment of motor symptoms in Parkinson's diseases]. / Medikamentöse Therapie der motorischen Symptome beim Morbus Parkinson.

Since the 1960s many substance classes have been introduced for treatment of idiopathic Parkinson's disease. The most important and effective medication is levodopa (L-dopa) always in combination with a decarboxylase inhibitor. In addition, dopamine agonists, monoamine oxidase B (MAO-B) inhibitors, catechol-o-methyltransferase (COMT) inhibitors, N­methyl-D-aspartate (NMDA) antagonists and very rarely anticholinergics are administered depending on the motor symptoms, age and a multitude of other factors. Fortunately, within the substance classes there are various preparations, which also have different effects. In order that the advantages of the individual medications can be exploited and undesired effects and interactions can be avoided, one must come to terms with the complex data and the pharmacology of the medication. In addition important aspects are interactions and reciprocal actions. In the foreseeable future, different substance classes are to be expected.

Anatomy and cervical dystonia : "Dysfunction follows form".

At first glance, cervical dystonia might be an illustration of the well-known proposition "function follows form". Nevertheless, cervical dystonia is a highly non-physiological condition, which cannot be reproduced by healthy subjects and does not respond to the usual physiological rules. "Dysfunction follows form" might be the most accurate aphorism to define cervical dystonia. Taking into account this situation and recent insights, the anatomic approach needs to be adapted to allow a better understanding of semiology and to improve botulinum toxin therapy. In this review dealing with a new approach to cervical dystonia, we develop some practical anatomical concepts concerning the head and neck complex. Knowledge of cervical spine and muscular dysfunctions in cervical dystonia is an essential stage in treating cervical dystonia patients with botulinum toxin.

[Intercultural adaptation of the AIMS in German language: A scale for abnormal involuntary movements]. / Interkulturelle Adaption der AIMS in deutscher Sprache : Eine Skala für abnorme unwillkürliche Bewegungen.

BACKGROUND: Dyskinesias are abnormal involuntary movements and occur across many movement disorders. In Parkinson's disease dyskinesias can be troublesome and are a determinant of the quality of life throughout the course of the disease. Assessment and rating of dyskinesias is thus important for clinical assessment of patients, as well as for academic studies and clinical trials. The abnormal involuntary movement scale (AIMS) is an English language standardised, reliable and validated scale to evaluate dyskinesias. In this article we present a linguistically validated German version of AIMS. METHODS: The intercultural adaptation of the German translation was performed following an internationally accepted procedure. Firstly, two neurologists independently translated the original into German. Taking both versions into account, a consensus version was agreed on by both translators and was tested on 10 patients. This preliminary German version was then independently translated back into the original language by two different neurologists, and again, a consensus version was agreed on. All translators then compared this English version to the original. Subsequently, the German version was linguistically modified until it resulted in a final German version, which was agreed on by all translators, deemed linguistically acceptable, and the translation back into English was considered to be as unambiguous as possible. This final German version of AIMS was applied to 50 patients in two different hospitals for diagnostic purposes and tested for feasibility and comprehension. RESULTS: In this paper, we present an intercultural adaptation of a linguistically validated German version of AIMS.

[Therapy and care of patients with chronic migraine: expert recommendations of the German Migraine and Headache Society/German Society for Neurology as well as the Austrian Headache Society/Swiss Headache Society]. / Therapie und Versorgung bei chronischer Migräne : Expertenempfehlung der Deutschen Migräne- und Kopfschmerzgesellschaft/Deutsche Gesellschaft für Neurologie sowie der Österreichischen Kopfschmerzgesellschaft/Schweizerischen Kopfwehgesellschaft.

Chronic migraine (CM) was first defined in the second edition of the International Headache Society (IHS) classification in 2004. The definition currently used (IHS 2006) requires the patient to have headache on more than 15 days/month for longer than 3 months and a migraine headache on at least 8 of these monthly headache days and that there is no medication overuse. In daily practice the majority of the patients with CM also report medication overuse but it is difficult to determine whether the use is the cause or the consequence of CM. Most the patients also have other comorbidities, such as depression, anxiety and chronic pain at other locations. Therapy has to take this complexity into consideration and is generally multimodal with behavioral therapy, aerobic training and pharmacotherapy. The use of analgesics should be limited to fewer than 15 days per month and use of triptans to fewer than 10 days per month. Drug treatment should be started with topiramate, the drug with the best scientific evidence. If there is no benefit, onabotulinum toxin A (155-195 Units) should be used. There is also some limited evidence that valproic acid and amitriptyline might be beneficial. Neuromodulation by stimulation of the greater occipital nerve or vagal nerve is being tested in studies and is so far an experimental procedure only.

[Gastrointestinal dysfunction in idiopathic Parkinson's disease]. / Gastrointestinale Störungen beim idiopathischen Parkinson-Syndrom.

Gastrointestinal dysfunction is frequent during all stages of Parkinson's disease. The entire gastrointestinal tract becomes involved and symptoms include sialorrhea, dysphagia (difficulties swallowing), delayed gastric emptying, absorption problems and constipation. These non-motor symptoms can be manifested even prior to the initial Parkinson diagnosis, i.e. during the so-called premotor phase of the disorder and may serve as prodromal markers of the early non-motor disease phase. In addition to causing patients major discomfort and a reduced quality of life, such gastrointestinal complaints can also negatively influence the therapy with antiparkinsonian medications. Thus, delayed gastric emptying is an important cause of unforeseen motor fluctuations.Gastrointestinal dysfunction is attributable in part to the presence of synucleinopathy (Lewy pathology) both in the dorsal motor nucleus of the vagus nerve, which supplies the parasympathetic innervation of the gut from the distal esophagus to the left colonic flexure, as well as in the intramural Meissner and Auerbach plexuses of the enteric nervous system (ENS). In all probability the development of the lesions in the lower brainstem and in the ENS precedes neurodegeneration of the dopaminergic nigrostriatal system. From a diagnostic standpoint, neurologists need not only a carefully taken patient history and the clinical findings but also esophagography (barium study), gastric scintigraphy and assessment of the colonic transit time. The therapeutic options for impaired upper gastrointestinal tract motility are still limited. Sialorrhea can be reduced by prescribing anticholinergics or injections of botulinum toxin and the peristalsis can be modulated by domperidone. In the lower gastrointestinal tract, constipation can be conservatively treated by using macrogol (polyethylene glycol) and, in the future, perhaps by serotonine (5-HT4) agonists.

Autonomic disorders in multiple sclerosis.

Multiple sclerosis is an inflammatory disease leading to disseminated lesions of the central nervous system resulting in both somatomotor and autonomic disturbances. These involve the central centers of the autonomic nervous system, as well as the automatic control and pathway systems. All autonomic functions may be disordered individually or in combined form. There is no other disease with a clinical picture so multifaceted. Besides cardiovascular dysfunctions disorders of bladder and rectum have become apparent. Somatomotor and autonomic disturbances occur with similar frequency; however the focused exam often heavily favors somatomotor symptoms. Autonomic disturbances should primarily be taken into account on history taking and clinical examination. Individual diagnosis and treatment is a secondary feature. Impairments of the autonomic nervous systems in multiple sclerosis are frequently overlooked.

Drug-induced impulse control disorders in Parkinson's disease.

Dopamine replacement treatment with excessive or aberrant dopamine receptor stimulation can cause behavioral disturbances in Parkinson's disease, comprising dopamine dysregulation syndrome, punding, and impulse control disorders. Common impulse control disorders are compulsive buying, pathological gambling, binge eating, hypersexuality, and compulsive reckless driving.

[Depression in Parkinson's disease--Part 2: Therapy and management]. / Depression beim idiopathischen Parkinson-Syndrom--Teil 2: Therapie und Management.

A good number of different methods and antidepressive agents are now available for the management of depressive symptoms, the efficacy of which has been confirmed by clinical studies. Various approaches--be it medication, electroconvulsive therapy (ECT), psychoeducation and psychotherapy--have also been developed to treat depression in patients with Parkinson's disease. Unfortunately, only a few controlled studies exist for this very specific group of patients. Systematic knowledge of treatment options, however, is lacking. Efficient management of depressive symptoms is absolutely indispensable considering the proven impact of a depression on the patients' quality of life. So far, more than half of the patients afflicted with Parkinson's disease and depression do not receive proper antidepressive therapy. This survey gives an overview on the pharmacological, somatic and psychological procedures of treatment applied in this group of patients, along with useful suggestions.

[Non-motor Symptoms Questionnaire and Scale for Parkinson's disease. Cross-cultural adaptation into the German language]. / Non-motor Symptoms Questionnaire und Scale für das idiopathische Parkinson-Syndrom. Interkulturell adaptierte Versionen in deutscher Sprache.

Idiopathic Parkinson's disease (PD) is a multisytem degenerative disorder. In addition to motor symptoms such as akinesia, rigidity and tremor, various non-motor symptoms occur, which are still insufficiently diagnosed. Moreover, the frequently used scales and scores do not adequately detect these non-motor symptoms. The Non-motor Symptoms Questionnaire (NMSQuest) is an established self-completed patient questionnaire with 30 qualitative questions covering all important non-motor symptoms of PD. The Non-motor Symptoms Scale (NMSScale) is a grade rating scale for estimating the frequency and severity of non-motor symptoms in PD. Since there are only original English versions of both questionnaires available, self-translated versions were frequently used or the questionnaires were not used at all in native German patients. We used international guidelines for cross-cultural adaptation of questionnaires to provide standard versions of both non-motor symptoms questionnaires in the German language.

[Clinical data of the prolonged-release formulation of ropinirole]. / Klinische Daten zur retardierten Formulierung von Ropinirol.

Ropinirole is a non-ergoline dopamine agonist with medium elimination half time, which has been licensed for the therapy of idiopathic Parkinson syndrome in mono- and add-on therapy for more than 10 years. Since 2008 a prolonged-release formulation has been available in Germany, which can be taken once daily. This formulation results in less plasma level fluctuations compared to the thrice-daily immediate-release formulation enabling smoother dopaminergic therapy with symptomatic efficacy day and night. Ropinirole PR has shown good efficacy and tolerability in controlled trials in monotherapy in early patients as well as in add-on studies in advanced patients. In a head-to-head comparison of both formulations as add-on therapy in advanced patients higher doses were achieved with ropinirole PR accompanied by a higher mean decrease of L-Dopa dose. Under these conditions significantly higher efficacy was observed. The titration regime of ropinirole PR is faster with significant efficacy versus placebo as early as in week 2. Especially in patients with pre-existing Parkinson-related poor sleep quality positive effects on sleep and nocturnal symptoms were shown.